Titanocene(III)-catalyzed 6-exo versus 7-endo cyclizations of epoxypolyprenes: Efficient control and synthesis of versatile terpenic building blocks

Article abstract of DOI:10.1002/chem.201302575

In this article, a complete study on the selectivity of titanocene(III) cyclization of epoxypolyprenes is presented. The requirements for the formation of six- or seven-membered rings during these cyclizations are determined, taking into account the different substitution pattern in the epoxypolyprene precursor. Thus, a complete selectivity to 6-exo or 7-endo cyclization process has been achieved, yielding mono-, bi-, and even tricyclic compounds, constituting a new and efficient access to this type of derivative. Additionally, this procedure opens the possibility to prepare excellent building blocks for the synthesis of polycyclic compounds with a trisubstituted oxygenated function, which is present in several natural terpenes.

Full text of DOI:10.1002/chem.201302575

FULL PAPER
DOI: 10.1002/chem.201302575
TitanoceneACTHNUTRGNEUG(N III)-Catalyzed 6-Exo Versus 7-Endo Cyclizations of
Epoxypolyprenes: Efficient Control and Synthesis of Versatile Terpenic
Building Blocks
Josꢀ Justicia,*[a] Tania Jimꢀnez,[a] Delia Miguel,[a] Rafael Contreras-Montoya,[a]
Rachid Chahboun,[a] Enrique ꢁlvarez-Manzaneda,[a] Daniel Collado-Sanz,[b]
Diego J. Cꢂrdenas,[b] and Juan M. Cuerva*[a]
Dedicated to Professor Rafael Robles on the occasion of his retirement
Abstract: In this article, a complete
study on the selectivity of titanocene-
ACHTUNGTRENNUNG(III) cyclization of epoxypolyprenes is
presented. The requirements for the
formation of six- or seven-membered
rings during these cyclizations are de-
termined, taking into account the dif-
ferent substitution pattern in the
complete selectivity to 6-exo or 7-endo
cyclization process has been achieved,
yielding mono-, bi-, and even tricyclic
compounds, constituting a new and ef-
ficient access to this type of derivative.
Additionally, this procedure opens the
possibility to prepare excellent building
blocks for the synthesis of polycyclic
compounds with a trisubstituted oxy-
genated function, which is present in
several natural terpenes.
Keywords: cyclic compounds · cyc-
lization · natural products · radicals ·
titanium
epoxy
G
a
Introduction
natural terpenes and has been attributed to a trapping of
the corresponding cationic intermediate by an external nu-
cleophile (usually a water molecule; Scheme 1, path B).[5]
Some selected examples are showed in Figure 1.
Natural terpenes are attractive goals in organic synthesis be-
cause of their structural complexities, relevant biological ac-
tivities and also as benchmarks for the development of new
synthetic protocols. In this context, bioinspired cationic cyc-
lizations of the corresponding starting polyprenes have been
extensively studied (Scheme 1, path A).[1] Nevertheless, cat-
It is also worth noting that biomimetic cationic-based pro-
tocols for the access to such structures (Scheme 1, path B)
are practically unknown owing to all the transient cationic
species that can be captured by the external nucleophile,
yielding the corresponding mixtures of products.[6] For that
reason, compounds containing such a structural moiety have
been usually synthesized by using undesirable additional
synthetic steps.[7] A recent example is the total synthesis of
myrrhanol A, in which this structural motif has been pre-
pared by epoxidation of an exocyclic double bond followed
by reduction with LiAlH4.[8] Other interesting solution is
ACHTUNGTRENNUNG
ionic cyclizations of simple unfunctionalized polyprenes,[1,2]
mainly developed by Goldsmith, Johnson, van Tamelen, and
Corey, present some drawbacks in general, such as low
yields and/or poor regio- and stereoselectivities. Therefore,
extra functional groups able to stabilize carbocationic inter-
mediates are usually required. This requirement is mandato-
ry when the desired target presents a thermodynamically un-
favorable exocyclic double bond in the final cyclic product.[3]
On the other hand, we can also find in nature compounds
presenting a tertiary oxygenated function instead of the cor-
responding alkene.[4] This functionality is very common in
À
based on controlled C H activation processes of the terpen-
ic parent structures. Unfortunately, this approach is not
nowadays general, and all the positions of the terpenic skel-
eton cannot be functionalized.[9]
This limitation of cationic approaches would be easily
overcome by using other propagating species such as
carbon-centered radicals, which have shown to be unreactive
towards oxygenated functions.[10] The use of bioinspired rad-
ical cascade cyclizations of the corresponding polyprenes
was introduced by the groups of Breslow and Julia more
than forty years ago.[11,12] Inspired by these precedents, our
group has developed an efficient and highly stereoselective
methodology for the radical cyclization of epoxypoly-
prenes[10,13] catalyzed by [TiClCp2][14–17] (Cp=cyclopenta-
dienyl). This radical approach presents complementary fea-
tures compared with previously known cationic cyclizations:
[a] Dr. J. Justicia, Dr. T. Jimꢀnez, Dr. D. Miguel, R. Contreras-Montoya,
Dr. R. Chahboun, Prof. E. ꢁlvarez-Manzaneda, Dr. J. M. Cuerva
Department of Organic Chemistry
Faculty of Science University of Granada, C. U. Fuentenueva s/n
18071 Granada (Spain)
E-mail: jjusti@ugr.es
jmcuerva@ugr.es
[b] D. Collado-Sanz, Prof. D. J. Cꢂrdenas
Department of Organic Chemistry, Faculty of Sciences
Universidad Autꢃnoma de Madrid, Tres Cantos, Madrid (Spain)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201302575.
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To our knowledge, methods for
the direct and simple prepara-
tion of this kind of natural ter-
penoids are not available. In
this article, we have determined
the substitution pattern re-
quired to control the 6-exo-trig
versus
7-endo-trig cyclization modes,
thus preparing new useful and
versatile building blocks in ter-
pene synthesis. It is also worth
noting that the oxygenated fea-
ture may be used for subse-
quent controlled transformations, thus yielding more elabo-
rated structures.
Scheme 1. Usual termination steps in terpene biosynthesis.
Figure 1. Selected examples of natural terpenoids presenting a trisubsti-
tuted oxygenated function.
Figure 2. Calculated transition states for 6-exo and 7-endo-trig cycliza-
tions of 6,7-epoxylinalyl acetate.
1) the presence of an exocyclic double bond in the final
products and 2) polycyclic compounds containing a 7-mem-
bered ring, inaccessible for “classical” cationic procedures,
could also be prepared.[18] Consequently, this protocol has
allowed the synthesis of several natural terpenes and
meroterpenes containing five, six, and seven-member
carbocycles.[12b]
The success of our approach resides in the high regiose-
lectivity in the addition of the transient radicals to the corre-
sponding double bonds. Thus, we demonstrated that geranyl,
farnesyl, and geranylgeranyl-derived epoxypolyprenes exclu-
sively undergo a sequence of 6-endo-trig cyclizations.[13a] On
the other hand, the final cyclization of linalyl, nerolidyl, and
geranyllinalyl-derived epoxypolyprenes takes place with an
unusual 7-endo-trig regiochemistry.[18] This unexpected cycli-
zation mode could be explained based on theoretical calcu-
lations.[18] In a chair-like transition state, the particular sub-
stitution pattern of these starting materials inevitably creates
a 1,3-diaxial interaction that presumably rises up the activa-
tion energy and, consequently, reduces the reaction rate of
the 6-exo cyclization process. In contrast, a seven-membered
ring can adopt conformations in which this diaxial interac-
tion is released (Figure 2).
Scheme 2. Working hypothesis.
Results and Discussion
We started our study by using simple linalyl-type derivatives
5–17 presenting diverse substitution patterns in the terminal
alkene. We selected a variety of substituents with different
steric and electronic features, which could affect the stability
of the transient radical. Therefore, we included as substitu-
ents simple alkyl chains (methyl and tetradecyl), oxygenated
allylic compounds, aromatic and cyclopropyl rings, a versa-
tile trimethylsilyl group, and carbonyl derivatives.[19] They
can be easily prepared using three possible procedures
(Scheme 3): A) direct nucleophilic addition of the corre-
sponding alkenyl lithium or magnesium derivative to com-
mercial 6-methyl-5-hepten-2-one (1) and subsequent epoxi-
dation, B) addition of the corresponding lithium or Grignard
acetylide to ketone 1 and subsequent epoxidation and parti-
Interestingly, if this hypothesis is correct the increase in
the steric hindrance in the alkene may disfavor the seven-
membered transition state biasing the reaction again to the
usual 6-exo-trig cyclization mode. In this situation, the final
products presenting a substitution pattern consisting on a
tertiary oxygenated function could be obtained (Scheme 2).
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Versatile Terpenic Building Blocks
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even with very similar yields.
The six-membered carbocycles
always showed a cis configura-
tion between the side chain at
C5 and the oxygenated group
at C6, with this latter function
being in an axial arrangement.
Consequently with the dia-
stereomeric mixtures used as
starting materials, two different
products with cis and trans rela-
tive configurations between the
C3 hydroxyl group and the side
chain at C5 can be obtained. In
Table 1, entries 2–11, we could
observe that cis products are
predominant, being the exclu-
sive products in some cases (en-
tries 7–8). The trans products
are only obtained with com-
pounds holding less bulky sub-
stituents at C5. Both cis and
Scheme 3. Procedures for the synthesis of starting epoxides 5–17; mCPBA=meta-chloroperbenzoic acid.
al reduction of the triple bond,[20] and C) ozonolysis of a
protected 6,7-epoxylinalyl derivative of 2 followed by Wittig
or Horner–Emmons olefination. These starting materials
present two stereocenters and are usually prepared as dia-
stereoisomeric mixtures. We took advantage of this fact
since we were also interested in the study of the influence of
the relative configuration at C3 and C6 on the cyclization
reaction. Moreover, the final diastereoisomeric carbocycles
could be isolated by using a simple column chromatography
separation. The synthesis of diastereo- and enantioenriched
starting materials is also possible. Thus, for example, epox-
ide (+)-(Z)-5 was prepared using commercial enantiopure
(À)-linalool by using a sequence of O-methylation, Shi
enantioselective epoxidation,[21] ozonolysis, and Wittig reac-
tion with a final diastereomeric excess (de) of 82%.
trans stereoisomers can be easily isolated and purified in
most of cases. These findings are consequent with a six-
membered transition state in which the less bulky acetate
group at C6 is preferably located in the axial position, yield-
ing two different diastereoisomers derived from the differ-
ent configuration in the epoxide. This assumption was con-
firmed by synthesizing enantio- and diastereomerically en-
riched epoxide (+)-(3S,6S)-5 (Table 1, entry 1), which gave
the corresponding stereoisomer (À)-(3S,6S)-18 in good
yield.
The yields were from moderate to excellent in both types
of cyclizations. The only exceptions were compounds with
aromatic substituents in a-position, which gave very low
yields (<10%), probably owing to the fact that generated
benzylic radical decomposes very rapidly in the reaction
media. Our group has described the benefits of water as an
additive in TiIII-mediated transformations, mainly as a radi-
cal reducing agent.[17a,22] Consequently with our previous
findings,[22] the addition of water (10 equiv) to the reaction
media promoted a significant increase in the corresponding
yield (Table 1, entry 7, 55%). Product 22, having an aryl
substituent, is interesting because it represents a new direct
access to natural meroterpenes. Although cationic and radi-
cal approaches to these skeletons have been described, nei-
ther of them yielded the oxygenated function at C6. This
tertiary acetate could be subsequently used as carbocation
precursor to continue increasing the complexity of the
molecule.[23]
We submitted this collection of epoxides (5–17) to the
TiIII-catalyzed radical cyclization using our previously descri-
bed procedure.[13a] It is based on the aprotic combination of
Me3SiCl/2,4,6-collidine and Mn, which is compatible with
oxiranes and capable of regenerating [TiCl2Cp2] (Cp=cyclo-
pentadienyl) from both [Ti(H)ClCp2] and oxygen-bonded ti-
tanium derivatives, including [TiACTHNUTRGEN(UNG OAc)ClCp2].
As can be observed in Table 1, complete regiochemical
control for the cyclization process is observed in all cases.
Substituents in the a position (Ra) always yielded 6-exo-trig
cyclization products (Table 1, entries 1–10), whereas sub-
stituents in b position (Rb) always generated the correspond-
ing 7-endo-trig cyclization products (Table 1, entries 12 and
13). The only exception was compound 17 (Table 1,
entry 14) in which both cyclizations were hindered, yielding
exclusively the uncyclized product 29.[16i] The configuration
of the alkene group does not seem to be relevant for the
stereochemistry of the cyclization, because of the same
products were obtained from pure (Z)-6 (Table 1, entry 2)
and a mixture of stereoisomers (E,Z)-6 (Table 1, entry 3),
Regarding the nature of the substituents, we could ob-
serve that not only simple alkyl chains but also functional-
ized ones are substrates of this transformation. The coinci-
dence of the final products in entries 2–3, and 6 (Table 1) is
expected considering the known behavior of titanocene
complexes towards simple and b-acetoxy substituted alkyl
radicals.[10,18] Moreover, the existence of transient radical in
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J. Justicia, J. M. Cuerva et al.
Table 1. TiIII-catalyzed cyclization of epoxides 5–17.[a]
Entry
Epoxide[b]
Cyclization products
Yield
[%][c]
1
2
3
(+)-(Z)-5[d]
(Z)-6
(À)-18
19
59
81[e]
78[e]
(E,Z)-6[f]
19
4
(Z)-7
20
43[e]
5
6
7
8
9
(Z)-8
(Z)-9
21
19
22
23
24
73[g]
84[h]
55[i]
43
AHCTUNGTRENN(GUN E,Z)-10
(E)-11
(Z)-12
46[e]
10
(E)-13
25
54[e]
11
12
14
15
26
27
41[i,j]
76
13
14
16
17
28
29
89
93
[a] See the Experimental Section for conditions; [b] 1:1 mixture of diastereoisomers; [c] referred to the starting diastereomeric mixture; [d] 91:9 mixture
of (3S,6S)/(3R,6S) diastereoisomers; [e] 4:6 mixture of a/b epimers at C3; [f] 55:45 mixture of E/Z stereoisomers; [g] 45:55 mixture of a/b epimers at C3;
ACHTUNGTRENNUNG
[h] 50:50 mixture of a/b epimers at C3; [i] the reaction was carried out in the presence of 10 equiv of water and 1.5 equiv of [TiCl2Cp2]; [j] 50:50 mixture
of E/Z stereoisomers.
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Versatile Terpenic Building Blocks
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these cyclizations is revealed by
the opening of the cyclopropyl
ring in Table 1, entry 5.[24] An-
other characteristic of TiIII-
mediated epoxypolyprene cycli-
zations, which distinguishes
them from other simple radical
cascade cyclizations, is that the
final products present an alkene
(Table 1, entries 1–6). Addition-
ally, the trimethylsilyl group is
also compatible with the reac-
tion conditions. In this case,
only one diastereoisomer was
able to cyclize owing to the
steric hindrance exerted by the
trimethylsilyl group. Finally, a
Scheme 4. Synthesis of higher epoxypoliprenes from (E)-geranyl acetone (30) and (E,E)-farnesyl acetone (31);
NBS=N-bromosuccinimide.
6-exo-dig cyclization (Table 1,
Table 2.
Entry
ACHTUNGTRENNUNG
entry 11) could also be obtained using compound
14 as starting material.[25] This final cyclic product
presents a high degree of functionality that can be
used in subsequent synthetic steps.
Yield
[%][c]
The excellent results obtained in the study of the
monocyclization of epoxides 5–17 encouraged us to
extend our research to more complex compounds.
Thus, we prepared a set of longer-chain epoxypoly-
prenes following similar methodology previously
depicted in Scheme 3, using in this case (E)-geranyl
acetone (30) and (E,E)-farnesyl acetone (31) as
starting materials (Scheme 4).
1
2
G
41
42
44
37
Epoxides 34–40, structurally similar to 5–17, were
submitted to our radical cyclization reaction cata-
lyzed by titanocene
in Table 2.
3
4
(E)-37
43
44
33
ACHTUNGTRENNUNG
(III).[13a] The results are depicted
The results obtained in the cyclization of epox-
ides 34–40 showed the same trends than those ob-
served in Table 1. Again, the chemical compatibility
with the different substituents allowed us an easy
access to interesting polycyclic building blocks in
terpene synthesis in few steps. In fact, alcohol de-
rived from the saponification of acetate group in
compound 41 (Table 2, entry 1) is an advanced in-
termediate in the synthesis of 8-epi-myrrhanol A,
an epimer of the natural polypodane triterpene iso-
lated from guggul-gum resin with anti-inflammatory
activity.[4f,26] Remarkably, only one stereoisomer un-
dergoes the cyclization in Table 2 (entries 1–3), thus
obtaining exclusively the 3S*,8S*,9R* diaster-
eoisomer. They present a cis relationship between
the oxygenated function at C8 and the side chain at
C9. The same stereoselection is observed in tricyclic
38
45[d]
5
6
39
40
45
46
54
77
7
A
47
21
[a] See the Experimental Section for the conditions; [b] 1:1 mixture of diastereoisom-
ers; [c] yields refer to the starting diastereoisomeric mixture; [d] 1:1 mixture of E/Z
isomers.
product 47. This stereochemical outcome is attributable to
the steric restrictions imposed by the first cyclization. The
success of the last cyclization is only possible if the oxygen-
ated function presents an axial arrangement. The flexibility
of monocyclic precursors, allowing other energetically ac-
ceptable transition states, is the responsible for the observa-
tion of both diastereoisomers in some monocyclization reac-
tions. Again, a 6-exo-dig cyclization took place when com-
pound 38 was used as starting material. Substrate (3S*,8S*)-
44 is an interesting building block for the synthesis of diter-
penes and norditerpenes due to its functionality. Although
the yields of these polycyclizations might seem modest, they
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J. Justicia, J. M. Cuerva et al.
are referred to the original diastereoisomeric mixture.
Taking into account the inability to cyclize of one of the dia-
stereoisomers present in the starting mixture, the reported
yields are more than acceptable for this kind of transforma-
tion. As it was previously observed in Table 1, mixtures of
cyclization products with different ring sizes were not ob-
tained, confirming the excellent control over the regioselec-
tivity of this reaction. In the case of 7-endo-trig cyclizations
(Table 2, entries 5 and 6), both epimers in C8 are apparently
able to cyclize, thus giving better yields.
Computational study of the 6-exo versus 7-endo regioselec-
tivity: To understand the origins of the observed selectivity,
we studied mono- and bicyclization processes with the aid of
computational methods. To this end, DFT calculations
(Gaussian 09)[27] using a B3LYP functional were carried
out.[16g,28] We will first discuss the influence of the position
of a methyl substituent in the monocyclization reaction
(Schemes 5–7). From Scheme 5 we can observe that for
a-substituted 3S*,6S* diastereoisomers I with Z configura-
tion in the alkene, the 7-endo-trig cyclization process is dis-
Scheme 5. Activation and reaction energies and Gibbs free energies calculated for cyclization reactions of model radicals: a) I and b) III. The TS for Ia
to Ic could not be found.
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Versatile Terpenic Building Blocks
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favored both kinetically (Ea =11.8 and 12.9 vs. 17.2 kcal
molÀ1) and thermodynamically (DE=À9.0 and À7.1 vs. À4.6
and À0.8 kcalmolÀ1) for both axial–axial (Ia) and equatori-
al–equatorial (Ib) precyclization conformers (Scheme 5a).
As a reference, we used the unfolded state because the pre-
folding energy significantly changes from one conformer to
another. Similar results were obtained with a-substituted
3S*,6R* diastereoisomer. In this case, the thermodynamics
of the process is again favorable to 6-exo-trig cyclization
(DE=À13.3 and À8.2 vs. À4.6 and À3.0 kcalmolÀ1) as well
as the kinetics (Ea =8.0 and 11.1 vs. 13.4 and 17.6 kcal
molÀ1). These theoretical data are therefore in complete
agreement with experimental results, in which we only ob-
serve six-membered carbocycles despite the relative configu-
ration of the starting epoxides. The reason of these remarka-
ble regioselectivity could be explain based on the transition
state structure. Thus, for example, in the seven-membered
transition state TSIb–IId the 1,2-interactions between methyl
simple examination of the corresponding transition states
clarifies the observed regioselectivity. For example, the exis-
tence of a substitution in the b position increases the activa-
tion energy of chair-like transition states TSIXa–Xa and TSIXb–
owing to the presence of four methyl groups in consecu-
Xb
tive positions (Figure 4). On the other hand, such unfavora-
ble 1,2 interactions do not exist in transition states TSIXa–Xc
and TSIXb–Xd. Moreover, the seven-membered rings can
adopt conformations in which the 1,3-diaxial interaction is
also released.
groups presumACHTUNGTRENNUNGably rises up the activation energy if we com-
pared with the observed 1,3-diaxial interaction in chair-like
transition states TSIa–IIa and TSIb–IIb (Figure 3). Similar trends
are also observed when 6-exo-trig cyclizations are favored.
Figure 4. Transition states for the cyclization of compound 15.
For simplicity, we restricted our study of bicyclization
processes to model radicals XIII, XV, XVII, and XIX
(Scheme 8). In this case, all the final products derive from
intermediate monocyclic radicals presenting a cis relation-
ship between the C3 hydroxyl group and the C5 alkyl side
chain. For the study of the second cyclization, a methyl
group was included as substituent in the a and b positions.
In the former case, we focused our attention on the Z
stereoACHTNUTRGNEiNUG somer owing to the similar results observed in the
monocyclization reaction. Also for simplicity, the titanoce-
ne(IV) alkoxide at C3 has been replaced in this study for a
simple hydroxyl group. Again, a-methyl substituted radicals
XIII and XV prefer to undergo a 6-exo-trig radical cycliza-
tion, which is kinetically (Ea =7.9 and 11.0 vs. 14.4 and
15.5 kcalmolÀ1) and energetically favored (DE=À10.7 and
À7.5 vs. À3.5 and 0.6 kcalmolÀ1). According to the experi-
mental results, we could observe that the energetic profile
for the radical cyclization of 3S*,8S* diastereoisomer XIII is
more favorable than the corresponding to the 3S*,8R* dia-
stereoisomer XV, thus justifying the stereodiscrimination ob-
served. The disfavored stereoisomer XV is then consumed
by secondary reactions before the required second cycliza-
tion. Both b-methyl substituted 3S*,8S* and 3S*,8R* diaster-
eoisomeric monocyclic radicals XVII and XIX presented
low activation barriers for the observed 7-endo-trig radical
cyclization. This theoretical result justifies the better yield
observed in the corresponding cyclizations, due to both dia-
stereoisomers being productive in the reaction.
Figure 3. Transition states for the cyclization of compound (Z)-6.
We also calculated the same processes with the corre-
sponding a-substituted diastereoisomers V and VII, present-
ing an alkene with E configuration (Scheme 6). In this case,
we can observe that the reaction profile is more complex,
but with both diastereoisomers the reaction yielding the six-
membered carbocycle is preferred, as we observed in the
corresponding reactions. Nevertheless, the kinetics and ther-
modynamics is less favorable than in structures presenting a
double bond with a Z configuration.
b-Methyl substituted diastereoisomers IX and XI were
also studied (Scheme 7). In agreement with the experimen-
tal results, only 7-endo-trig cyclizations were energetically
favored for both diastereoisomers. Moreover, 7-endo-trig
cyclizations are also kinetically favored by 5–6 kcalmolÀ1. A
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J. Justicia, J. M. Cuerva et al.
Scheme 6. Activation and reaction energies and Gibbs free energies calculated for cyclization reactions of model radicals: a) V and b) VII.
Conclusion
of desired cyclization. This control is completely determined
by the position of different substituents in the starting acy-
clic polyprenic chain, which drives the reaction exclusively
to form six- or seven-membered carbocycles. Remarkably,
the synthesized 6-membered carbocycles have a trisubstitut-
In this article we have presented an efficient methodology
for the preparation of versatile building blocks for terpene
synthesis, based on the highly efficient control over the type
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Versatile Terpenic Building Blocks
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Scheme 7. Activation and reaction energies and Gibbs free energies calculated for cyclization reactions of model radicals: a) IX and b) XI.
was freshly distilled from P2O5. Products were purified by flash chroma-
tography on Merck silica gel 50. Yields refer to analytically pure samples.
NMR spectra were recorded by using NMR (300, 400 and 500 MHz)
spectrometers. 1H and 13C NMR spectra of compounds 32,[29] and 33[30]
matched with those previously described.
General procedure for TiIII-catalyzed bioinspired cyclizations: Strictly de-
ed oxygenated function, which is present in numerous natu-
ral terpenes, and bothersome to prepare by using other
methodologies. The excellent control found in these reac-
tions has been also confirmed using extensive theoretical
calculations. Currently, we are performing additional studies
to extend our method for the cyclization of higher size rings,
oxygenated THF (20 mL) was added to
a mixture of [TiCl2Cp2]
and its application in the synthesis of complex natural prod-
ucts.
(0.2 mmol) and Mn dust (8 mmol) under an Ar atmosphere and the sus-
pension was stirred at room temperature until it turned lime green (after
about 15 min). Then, a solution of epoxide (1 mmol), 2,4,6-collidine
(7 mmol) in THF (2 mL), and Me3SiCl (4 mmol) were added and the
mixture was stirred for 16 h. The reaction was then quenched with 2N
HCl and extracted with EtOAc. The organic layer was washed with
brine, dried (anhydrous Na2SO4) and the solvent removed. Products 18–
29 and 41–47 were isolated by flash chromatography of the residue
(hexane/EtOAc) and characterized by spectroscopic techniques. Results
Experimental Section
General details: Deoxygenated solvents and reagents were used for all
reactions involving [TiClCp2]. THF was freshly distilled from Na. CH2Cl2
Chem. Eur. J. 2013, 00, 0 – 0
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are depicted in Tables 1 and 2. Compound 47 was purified by
using 15% AgNO3/silica gel.
Acknowledgements
We thank the Regional Government of Andalucꢅa (project P09-
FQM-4571), the Spanish MICINN (project CTQ-2011.22455), and
the University of Granada (CEI-BIOTIC) for financial support,
and the Centro de Computaciꢃn Cientꢅfica-UAM for computation
time. T.J. thanks MICINN for her FPU fellowship. D.M. thanks
the Regional Government of Andalucꢅa for her contract.
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Versatile Terpenic Building Blocks
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Received: July 3, 2013
Published online: && &&, 2013
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Versatile Terpenic Building Blocks
FULL PAPER
Terpenes
J. Justicia,* T. Jimꢀnez, D. Miguel,
R. Contreras-Montoya, R. Chahboun,
E. ꢁlvarez-Manzaneda,
D. Collado-Sanz, D. J. Cꢂrdenas,
J. M. Cuerva* ................. &&&& — &&&&
Ti for terpenes: A complete study on
the selectivity of the titanoceneACTHNUTRGNEUG(N III)
cyclization of epoxypolyprenes is pre-
sented. The requirements for the for-
mation of six- or seven-membered
rings during these cyclizations are
determined, yielding a complete selec-
tivity to the 6-exo or 7-endo cyclization
process (see scheme). This procedure
opens the possibility to prepare excel-
lent building blocks for the synthesis
of polycyclic compounds.
TitanoceneACTHUNRTGNEUNG(III)-Catalyzed 6-Exo
Versus 7-Endo Cyclizations of Epoxy-
polyprenes: Efficient Control and
Synthesis of Versatile Terpenic
Building Blocks
Chem. Eur. J. 2013, 00, 0 – 0
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